Benzomorphane

Pentazocine (( )-2 -hydroxy-5,9-dimethyl-2 (3,3-dimethylallyl)-6,7-benzomorphan, Win 20,228, Talwin, LlXa). 

Grauert, M., Bechtel, W. D., Ensinger, H. A., Merz, H., Carter, A. J. Synthesis and structure-activity relationships of 6,7-benzomorphan derivatives as antagonists of the NMDA receptor-channel complex, J. Med. Chem. 1997, 40, 2922-2930... 

A mixture of 59.5 g (0.2 mol) 2-(4-methoxybenzyl)-l,3,3-trimethyl-4-piperidone hydrochloride and 53.8 g (0.4 mol) of aluminum trichloride and 54.0 g of nitrobenzene in 1500 ml of dry benzene are boiled under reflux for 1 h. After cooling the reaction mixture is extracted with 750 ml 4 N sodium hydroxide solution, the temperature being maintained below 35°C. The organic phase is separated and extracted with 750 ml 1 N hydrochloric acid. The acid aequeous phase is rendered alkali by the addition of 100 ml 25% ammonia and extracted three times with 250 ml chloroform. The collected chloroformic phases are dried with sodium sulfate and evaporated under reduced pressure. The residue, 46.7 g, is converted into the hydrochloride by reaction with iso-propanol/HCI and crystallized from a mixture of methanol and ethylacetate. 44.6 g of the 5-hydroxy-2 -methoxy-2,9,9-trimethyl-6,7-benzomorphan hydrochloride are obtained, melting point 233-236° C (dec.). 

A solution of 4.68 g (44 mmol) cyanogenbromide in 28 ml chloroform are added drop-wise within 5 min to a solution of 8.25 g (30 mmol) 2, 5-dimethoxy-2,9,9-trimethyl-6,7-benzomorphan in 20 ml dry ethanol free chloroform. After boiling for 4 h under reflux the solution is concentrated under reduced pressure, the residue dissolved in 150 ml toluene, washed twice with 50 ml 2 N hydrochloric acid and once with water, dried over sodium sulfate and evaporated to dryness under reduced pressure to yield 7.82 g 2-cyano-2, 5-dimethoxy-2,9,9-trimethyl-6,7-benzomorphan. The obtained residue is dissolved in 40 ml of dry peroxide-free tetrahydrofuran and the solution added drop-wise under a nitrogen atmosphere over a period of 20 min to a suspension of 2.10 g (61.7 mmol) of lithium aluminum hydride in 85 ml tetrahydrofuran. After boiling for 3 h under reflux and cooling, 2.1 ml water, 1.6 ml 4 N sodium hydroxide solution, 7.3 ml water and 85 ml chloroform are added sequentially. After stirring for 30 min the obtained hydroxide is filtered off over hyflo. The precipitate is stirred 3 times with 50 ml chloroform/butanol (9 1). The filtrate washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue is converted into the hydrochloride and crystallized from methanol/ethylacetate to yield 4.9 g of the 2, 5-dimethoxy-9,9-dimethyl-6,7-benzomorphan hydrochloride, melting point 220-222°C (dec.). 

A solution of ethanethiol in dimethylformamide (DMF) are added dropwise to a suspension of sodium hydride (55% suspension in oil) in dry DMF. The obtained suspension is stirred for a further 45 min and a solution of 2, 5-dimethoxy-9,9-dimethyl-6,7-benzomorphan in 190 ml of dry DMF are added dropwise over 20 min. The initially formed volatile components are distilled off and the reaction mixture heated until the DMF boils. After boiling for 6 h under reflux the reaction mixture is concentrated under reduced pressure and the residue taken up in toluene and 2 N hydrochloric acid. The acid aqueous phase is made alkaline with 25% ammonia and extracted 3 times with chloroform/butanol (8 2). After evaporation of the organic phase, the residue is converted into the 9,9-dimethyl-2, 5-dihydroxy-6,7-benzomorphan hydrochloride, (crystallized from isopropanol). 

A mixture of 9,9-dimethyl-2, 5-dihydroxy-6,7-benzomorphan hydrochloride, calcium carbonate and toluene-4-sulfonic acid but-3-ynyl ester in dimethylformamide is heated and subsequently concentrated under reduced pressure. The residue is taken up in a mixture of water and chloroform (1 1) and the aequeous phase extracted twice with chloroform/butanol (9 1). The combined organic phases are concentrated under reduced pressure to give the... 

Beckmann rearrangement of C-ring ketones (26 and 27) prepared via a 2-tetralone (Scheme 4.3) afforded a route to 6,7-benzomorphans that were otherwise difficult to synthesize. (13"14a) The 11a- and 11/3-methylnorbenzomor-phans (29) were prepared in this way. 

Tetralone intermediates also offer approaches to 6,7-benzomorphan synthesis. The 1-tetralone (35, Scheme 4.4) may be prepared in five stages from 1-cyano-l-phenylmethane (a-methylphenylacetonitrile) (hydratropo-nitrile) (30).(7) Significant yield losses may occur during the reverse-addition LAH reduction of (31). From the tetralone (35) the synthesis proceeds in a... 

Arylbenzomorphans may be viewed as possessing pharmacophoric patterns relating to both 6,7-benzomorphans and methadone. Walker and... 

The presence of an 11-methyl group in 6,7-benzomorphans has been demonstrated to enhance analgesic responses. Synthetic approaches to benzomorphans lacking a 6-alkyl substituent from pyridines usually fail as a consequence, a twelve-step 1-tetralone route was developed(19) (Scheme 4.7). 

Other substituted piperidines, particularly piperidinols, have been exploited as benzomorphan precursors. The first 6,7-benzomorphan lacking a 6-alkyl substituent, the parent heterocycle, was reported by May et al. in 1968<43,44) in a synthesis from 2-cyano-4-phenylpyridine (102) (Scheme 4.15). The 2-carbomethoxypiperidine (103) was prepared readily, but it proved resistant to direct cyclization to 3-methylbenzomorphan-l-one (105) with polyphosphoric acid, presumably because the more stable 2,4-diequatorial isomer is not favorable for ring closure for geometric reasons. Hydrolysis to the corresponding acid (104), however, gives an intermediate that closes to 105 in 94% yield. The parent heterocycle 106 is produced by standard techniques. 

Most attempts to design narcotic antagonists based on 4-phenylpiperidine by linking the basic center to groups such as allyl, substituted allyl, and cyclopropyl methyl (CPM) that confer such properties on fused cyclic systems as possessed by morphine and 6,7-benzomorphans have led to agonists that have no power to block opiate receptors examples include TV-allyl derivatives of norpethidine and norprodine (18)34 and the TV-3-chloroallyl reversed ester 19.(56) Essentially similar results were found for a group of TV-substituted... 

SYNS 2-DIMETHYL LLYI 5,9-DIMETHY1 2 -HYDRO-XYBENZOMORPHAN 2-(3,3-DIMETHYLALLYL)-2, 2 -HYDROXY-5,9-DlMETHYL-6,7-BENZOMORPHAN FORTALGESIC FORTALIN FORTRAL 1,2,3,4,5,6-HEXAHYDRO-6,ll-DIMETHYI 3-(3-METHYL-2-BUTENYL)-2,6-METHANO-3-BENZAZOCINE 2 -HYDROXY-5,9-DIMETHYL-2-(3,3-DIMETHYLALLYL)-6,7-BENZOMORPHAN dl-2 -HYDROXV-5,9-DIMETHYI 2-(3,3-DIMETH i LALLYL)-6,7-BENZOMORPHAN II-C-2... 

Pentazocine, USP. Pentazocine. 1.2.3.4.S.6-hcubv-dro-cfs-6,11 -dimethyl-3-(3-mc ihyl-2-butenyl)-2.6-nKili ano3-benzazocin-8-ol. ci.v-2-dimethylallyl-5.9-dimcthyl-l -hydroxy-6,7-benzomorphan (Talwin). iKCurs as a uhic crystallinc powder that is insoluble in water and sparingh". soluble in alcohol. It forms a prly soluble hyclnx lilnidt salt, but is readily soluble as the lactate. 

In this study, as a first step in modeling opiate receptor interactions, we have considered the interaction of an ammonium ion and methyl sulfate or phosphate with the series of compounds shown in Figure 1. These compounds, as N-substitutents in rigid opiates such as 5,9 dimethyl, 2 hydroxy, 6,7 benzomorphans, exhibit a broad spectrum of pharmacological behavior from... 

Antagonist potencies measured in vitro in the guinea pig ileum system or in vivo by extent of withdrawal in addicted animals should closely parallel the affinity of opiates for the receptor site. Both antagonist potencies and stero-specific binding constants have been measured for a number of N-substituted 5,9 dimethyl 2 hydroxy 6,7 benzomorphan analogues (14, 15, 32). Table III gives these values for the compounds studied and shows the extent of correlation between the known affinities and potencies for four analogues. 

Benzomorphans. The 9fianalog (3a) of the isomeric 2,9-dimethyl-2 -hydroxy-6, 7-benzomorphans was 4 times as potent (EDjq=1.1 mg/kg) as the 9aanalog (3b) by the hot plate test. 13... 

Clarke and his co-workers have also prepared a nvimber of carbamates in the 5-phenyL series, one of these, 2-carbox-amide-2 -hydroxy-5-phenyl-6,7-benzomorphan, had weak analgesic activity in the hot-plate test and did not substitute for morphine in the addicted monkey. This compound has been reported to have codeine-like analgesic activity in man. ... 

A classification scheme has been suggested. Those receptors that bind the (-F )-6,7-benzomorphans, such as (-F)-NANM and (-F )-Pentazocine, with high affinity and those which bind these ligands with low affinity are designed as CT, and CTj respectively (Quirion et al., 1992). Other sites with a distinct pharmacological profile versus the previously defined subtypes appear to exist. A series of l-phenyl-3-aminotetralines (PATs), exemplified by Hj-PAT was found to stimulate tyrosine hydroxylase activity and dopamine synthesis through interaction with a novel aj receptor (Wyrick and Booth, 1995). 

Booth, R.G., Baldessarini, R.J., 1991. (+ )-6,7-Benzomorphan sigma ligands stimulate dopamine synthesis in rat corpus striatum tissue. Brain Res. 557, 349-352. 

The 8-keto benzomorphan derivative lb was prepared from ( - )5,9-a-dimethyl-2 -hydroxy-6,7-benzomorphan... 

Structure related to morphine. Synthesis of. alpha.-2-N-heptyl-2 -hydroxy-5,9-dimethyl-6,7-benzomorphan from 3,4-lutidine. II... 

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